RESUMO
BACKGROUND AND AIMS: Vascular calcification (VC) is an intricate active process, significantly controlled by vascular smooth muscle cells (VSMCs). Mitochondrial dysfunction plays a pivotal role in VC and VSMCs osteoblastic transformation. We previously reported that decreased levels of Irisin were independently associated with VC in hemodialysis patients. The present study aimed to investigate the role of Irisin in VC, especially in VSMCs osteoblastic transformation and mitochondrial function. METHODS: In vitro, VSMCs calcification was induced by ß-glycerophosphate, while in vivo VC was triggered by adenine and high phosphorus diet. Alizarin red, Von Kossa staining, and calcium and Alp activity were performed to test VC. Western blot and immunohistochemical staining were employed to analyze the expression of proteins associated with VSMCs osteoblastic transformation and AMPK signaling. Mitochondrial membrane potential (MMP) and structures were observed by immunofluorescence staining. RESULTS: Irisin alleviated VSMCs calcification induced by ß-glycerophosphate. Mechanistically, Irisin activated AMPK and downregulated the expression of Drp1, further alleviating mitochondria fission and VSMCs osteoblastic transformation. In vivo, Irisin decreased serum creatinine, urea and phosphorous levels in chronic kidney disease (CKD) mice. Importantly, Irisin treatment postponed CKD-associated VC with the upregulation of α-Sma and p-AMPK expression, and the downregulation of Runx2 and Drp1 expression. CONCLUSIONS: Our results firstly reveal that Irisin inhibits CKD-associated VC. Irisin suppresses VSMCs osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling.
Assuntos
Fibronectinas , Insuficiência Renal Crônica , Calcificação Vascular , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Dinaminas/metabolismo , Fibronectinas/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Calcificação Vascular/metabolismoRESUMO
The current study aimed to investigate the association between telomere length in peripheral blood leukocytes and kidney function in various age groups of a healthy population. A total of 139 healthy individuals were divided into five groups according to their age: 3544, 4554, 5564, 6574 and >75 years old. Peripheral blood leukocytes were obtained and the telomere restriction fragment (TRF) length was assayed using a digoxigeninlabeled hybridization probe in Southern blot assays. Laboratory assays of kidney function were also performed. A correlation was observed between TRF length and age (r=0.314, P<0.001), with the telomere length of the individuals >75 years group being significantly shorter than the telomere length of the 3544, 4554 and 5564 years age groups (P<0.05). By contrast, the TRF length for males versus females did not differ for any of the age groups, while a correlation was observed between TRF length and serum levels of cystatin C (r=0.195, P<0.05). There was also a correlation between TRF length and glomerular filtration rate (r=0.184, P<0.05). The current study demonstrated that in this cohort, leukocyte telomere length reduced with age and was correlated with serum levels of cystatin C and glomerular filtration rate. Therefore, TRF length is associated with kidney function and may serve as a marker of aging.